Azole γ-Peptides Helix Switching via Heterocycle Substitutions

Precise control of peptide backbone folding through non-covalent interactions remains a major challenge in foldamer design. In this work, we demonstrate that heteroatom substitutions program conformational switching in azole γ-peptides by tuning intrinsic stereoelectronic effects within heterocyclic γ-amino acids. Conformationally constrained thiazole- and oxazole-based γ-amino acids were designed to adopt conformations driven by either a C₉ or a C₇ intramolecular H-bond depending on key 1,4-X···O interactions (X = S or N). We previously showed that thiazole-based oligomers form a well-characterized canonical 9-Helix. Here, permutation of the sulfur and nitrogen atoms within the heterocycle induces a stretched helical structure with alternating C₇-turns and residues in extended conformations. This unusual topology arises from competition between seven-membered intra-residue H-bonds and attractive S···N electrostatic-chalcogen interactions. Reversing this effect through an S→O substitution affords oxazole-derived oligomers that adopt a stable 7-Helix stabilized by a continuous seven-membered H-bond network in solution. These findings show that simple heteroatom permutation or substitution allows control over heterocyclic γ-peptide folding, thereby expanding opportunities for foldamer design in molecular recognition, catalysis, and biomedical applications.